With nearly 116 mln people suffering from chronic pain in the US alone and the global market projected to reach $83 bln by 2024, there is both a major unmet medical need and a significant commercial opportunity. Dominated by opioid drugs, this field also suffered from alarming consequences of opioid drug overuse and misuse. Antagonists acting at TRPV1 receptor have long been recognized as one of the most promising novel classes of non-opioid analgesics. Several drug companies have developed highly selective and potent compounds. Initial tests in humans have confirmed pharmacodynamic profile expected for this class of agents (i.e. analgesia). However, despite an overall good safety and tolerability, there were significant effects on thermoregulation resulting in clinically meaningful hyperthermia and partial loss of heat sensitivity. These effects have led to the discontinuation of essentially all of the advanced programs in the field of TRPV1 antagonists. In this regard, and in line with funding opportunity RFA-DA-19-019, the current application proposes to conduct a set of preclinical proof of concept studies in rats to support the claims that, at doses that have minimal, clinically acceptable or negligible impact on cardiovascular function, a2 adrenoceptor agonists can diminish thermoregulatory effects of TRPV1 receptor antagonists. In Phase 1, we will demonstrate that (Aim 1) presynaptically acting a2 adrenoceptor agonists such as lofexidine can prevent or diminish the hyperthermic responses to TRPV1 receptor antagonists; (Aim 2) at the doses controlling thermoregulatory effects of TRPV1 receptor antagonists, a2 adrenoceptor agonists have minimal or acceptable effects on hypotension.